Project Summary/Abstract Chronic pain is the most common complaint of patients, affecting over 100 million Americans, and costing the nation more than $650 billion/year in medical treatment and lost productivity. Most chronic pain patients are resistant to pharmaceutical or surgical therapies, in large part because the underlying pathophysiology of their chronic pain condition is unknown. The ultimate goal of this research program is to rectify this deficiency. Most spinal cord pain-related afferents target the parabrachial nuclear complex (PB), which then projects to multiple pain-related cortical and subcortical targets. New preliminary data indicate that inhibitory inputs from the central nucleus of the amygdala (CeA) to PB are reduced in a rodent neuropathic pain model: chronic constriction of the infraorbital nerve (CCI). This reduced inhibition dramatically `amplifies' both spontaneous and evoked PB neural activity. As a consequence, there is increased PB excitation of several pain-related nuclei, including the rostral ventral medulla (RVM), a key node of the descending pain modulation system. Based on this exciting new evidence we hypothesize that chronic pain results from the development of a pathologic positive feedback network: Reduced inhibition from CeA to PB ?> amplified PB activity ?> increased activation of RVM neurons ?> increased activation of nociceptive neurons in the spinal cord. With the use of electrophysiological recordings from intact rodents and from brain slices, and taking advantage of behavioral approaches, optogenetics and pharmacogenetics, we will directly test this overarching hypothesis. Specifically, we will (1) Test the hypothesis CCI causes a progressive and significant reduction of inhibitory inputs to nociceptive PB neurons that project to RVM, and dramatically increases their firing; (2) Test the hypothesis that amplified PB activity is due to reduced inhibition from CeA.; (3) Test the hypothesis that reduced CeAI inhibition to PB is causally related to the development of CCI-Pain. The anticipated findings are expected to reveal novel mechanisms for the development of chronic pain, and may lead to development of novel therapies to ameliorate, and perhaps even prevent, this devastating condition.